Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria.
Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria.
Acta Neuropathol Commun. 2023 Jun 18;11(1):98. doi: 10.1186/s40478-023-01595-w.
X-linked adrenoleukodystrophy (X-ALD), the most frequent, inherited peroxisomal disease, is caused by mutations in the ABCD1 gene encoding a peroxisomal lipid transporter importing very long-chain fatty acids (VLCFAs) from the cytosol into peroxisomes for degradation via β-oxidation. ABCD1 deficiency results in accumulation of VLCFAs in tissues and body fluids of X-ALD patients with a wide range of phenotypic manifestations. The most severe variant, cerebral X-ALD (CALD) is characterized by progressive inflammation, loss of the myelin-producing oligodendrocytes and demyelination of the cerebral white matter. Whether the oligodendrocyte loss and demyelination in CALD are caused by a primary cell autonomous defect or injury to oligodendrocytes or by a secondary effect of the inflammatory reaction remains unresolved. To address the role of X-ALD oligodendrocytes in demyelinating pathophysiology, we combined the Abcd1 deficient X-ALD mouse model, in which VLCFAs accumulate without spontaneous demyelination, with the cuprizone model of toxic demyelination. In mice, the copper chelator cuprizone induces reproducible demyelination in the corpus callosum, followed by remyelination upon cuprizone removal. By immunohistochemical analyses of oligodendrocytes, myelin, axonal damage and microglia activation during de-and remyelination, we found that the mature oligodendrocytes of Abcd1 KO mice are more susceptible to cuprizone-induced cell death compared to WT mice in the early demyelinating phase. Furthermore, this effect was mirrored by a greater extent of acute axonal damage during demyelination in the KO mice. Abcd1 deficiency did not affect the function of microglia in either phase of the treatment. Also, the proliferation and differentiation of oligodendrocyte precursor cells and remyelination progressed at similar rates in both genotypes. Taken together, our findings point to an effect of Abcd1 deficiency on mature oligodendrocytes and the oligodendrocyte-axon unit, leading to increased vulnerability in the context of a demyelinating insult.
X 连锁肾上腺脑白质营养不良（X-ALD）是最常见的遗传性过氧化物酶体疾病，由 ABCD1 基因突变引起，该基因编码一种过氧化物酶体脂质转运蛋白，将长链脂肪酸（VLCFAs）从细胞质转运到过氧化物体中进行β-氧化降解。ABCD1 缺乏导致 X-ALD 患者的组织和体液中 VLCFAs 积累，表现出广泛的表型。最严重的变异型是脑型 X-ALD（CALD），其特征是进行性炎症、少突胶质细胞的丧失和脑白质脱髓鞘。CALD 中的少突胶质细胞丧失和脱髓鞘是由原发性细胞自主缺陷或少突胶质细胞损伤引起，还是由炎症反应的继发性效应引起，目前仍未解决。为了探讨 X-ALD 少突胶质细胞在脱髓鞘病理生理学中的作用，我们将 ABCD1 缺陷的 X-ALD 小鼠模型（该模型中 VLCFAs 积累而无自发性脱髓鞘）与毒蕈碱诱导的脱髓鞘模型相结合。在小鼠中，铜螯合剂铜锌灵可在胼胝体中诱导重现性脱髓鞘，然后在去除铜锌灵后进行髓鞘再生。通过对脱髓鞘和再髓鞘过程中的少突胶质细胞、髓鞘、轴突损伤和小胶质细胞激活进行免疫组织化学分析，我们发现与 WT 小鼠相比，ABCD1 KO 小鼠的成熟少突胶质细胞在早期脱髓鞘阶段对铜锌灵诱导的细胞死亡更为敏感。此外，在 KO 小鼠中，这种效应与脱髓鞘过程中更严重的急性轴突损伤相对应。在治疗的两个阶段，ABCD1 缺乏均不影响小胶质细胞的功能。此外，两种基因型的少突胶质前体细胞的增殖和分化以及再髓鞘化的进展速度相似。总之，我们的研究结果表明 ABCD1 缺乏对成熟少突胶质细胞和少突胶质细胞-轴突单元有影响，导致在脱髓鞘损伤的情况下易损性增加。
